2HRR

Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Tabun (GA)

2HRR の概要

• エントリーDOI: 10.2210/pdb2hrr/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: Liver carboxylesterase 1, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, R-ETHYL N,N-DIMETHYLPHOSPHONAMIDATE, ... (7 entities in total)
• 機能のキーワード: hydrolase, carboxylesterase, tabun
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 179526.67

構造登録者

Fleming, C.D.,Redinbo, M.R. (登録日: 2006-07-20, 公開日: 2007-05-01, 最終更新日: 2024-12-25)

主引用文献

Fleming, C.D.,Edwards, C.C.,Kirby, S.D.,Maxwell, D.M.,Potter, P.M.,Cerasoli, D.M.,Redinbo, M.R.
Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun.
Biochemistry, 46:5063-5071, 2007

PubMed Abstract: The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.

PubMed: 17407327
DOI: 10.1021/bi700246n

実験手法

X-RAY DIFFRACTION (2.7 Å)